Project Summary: Understanding sleep problems in the Autism Spectrum through Shank3. Autism Spectrum Disorder (ASD) is the most prevalent neurodevelopmental disorder in the US. Several studies have demonstrated that sleep problems occur in ASD at a much higher rate than in typical development. Sleep problems predict the severity of ASD core diagnostic symptoms (e.g., repetitive behaviors and social/communication deficits) as well as other associated problems (e.g., tantrums and aggression). Therefore, understanding the mechanism behind why individuals with ASD have difficulties with sleep holds great promise toward designing interventions to improve quality of life of patients and their families. Study of monogenic syndromes with a high rate of ASD as well as animal models carrying single gene mutations has proven valuable to understand mechanisms underlying ASD. In this context, in my preliminary studies I investigated the role of Shank3, a high confidence ASD gene candidate, in the regulation of sleep. Complete deletion of Shank3 leads Phelan McDermid Syndrome (PMS), a rare disease strongly associated with ASD. Using data on sleep habits obtained from the PMS International Registry, I found that problems with sleep onset are present in >50% of patients. I then performed electrophysiological recordings in Shank3 mutant mice, and found that mutants sleep less than wild-type (WT) mice following sleep deprivation (SD).!Given what we know about how sleep need is regulated, these results can be explained through two alternative hypotheses: 1) Shank3 mutants do not accumulate increased sleep need after SD (they are not as sleepy) or 2) Shank3 mutants do accumulate increased sleep need after SD but have difficulties transitioning from wake to sleep (they are unable to fall asleep when sleepy). The goal of this K01 Career Development award is to obtain additional training and perform additional experiments to differentiate between these two alternative hypotheses as a starting point to an independent line of research. In specific aim 1, I will pursue additional training to investigate the role of Shank3 in regulating sleep need using electrophysiology. In specific aim 2, I will build on previous studies I conducted as a postdoctoral fellow and as a PI to investigate the biomolecular mechanism linking Shank3 with disturbed sleep. My mentoring team includes Dr. John Roll, the Vice- Dean of Research of the College of Medicine, as well as senior scientists from the world-renowned Sleep and Performance Research Center (SPRC) at WSU: Dr. Hans Van Donguen, Dr, Greg Belenky and Dr. Jonathan Wisor. They will ensure the success of my training plan with the environment and resources provided by the College of Medicine and the SPRC at WSU. The proposed training will complement my prior expertise in behavior, molecular biology and genomics to help me establish a research program as an independent investigator that will focus on using genomic and candidate gene approaches to understand the interaction between genes and sleep in ASD.